CN1171083C - 光学衍射生物传感器 - Google Patents
光学衍射生物传感器 Download PDFInfo
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- CN1171083C CN1171083C CNB988122553A CN98812255A CN1171083C CN 1171083 C CN1171083 C CN 1171083C CN B988122553 A CNB988122553 A CN B988122553A CN 98812255 A CN98812255 A CN 98812255A CN 1171083 C CN1171083 C CN 1171083C
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Abstract
本发明提供了一种探测和定量测定存在于介质中的被分析物的廉价而又灵敏的装置和方法。该装置包括金属涂膜(20)，其上印制有特定的、预定型式的、专用于被分析物的受体(25)。当目标分析物与印制有受体的塑料膜选定部位相接触时，可以通过被分析物的物理尺寸及其确定而精确的放置，产生透射光和/或反射光的衍射。进而产生一个很容易被肉眼所观察到，或视需要用一个传感器观察到的衍射图象。
Description
技术领域
本发明涉及分析物传感器领域，更准确地说本发明涉及金属薄膜上的微触点印制胶合物以其制成光学衍射生物传感器的领域。
本发明背景
微触点印刷是形成微米或亚微米侧向尺寸的有机单分子层图形的一种技术。该项技术为形成某些类型图形提供了实验上的简易性和灵活性。在已有技术中，微触点印刷利用自组装的长链烷烃硫醇盐单分子层在黄金或其它金属上形成有机结构。这些图形起到纳米保护层的作用，以防止依托的金属被适当配制的腐蚀剂所侵蚀，或允许在图形的亲水区有选择地放置液体。通常，利用烷烃硫醇作为“墨水”可形成尺寸小于1微米的自组装单分子层的图形，并可利用高弹体“印模”将其印制在依托的金属上。印模是利用光学或X-射线微平板印刷术或其它技术制备的靠模模压硅橡胶制成的。(参见美国专利申请系列Nos.08/654,993；08/769,594；08/821,464；08/707,456和08/768,449，在这里将其全部引入作为参考文献)
微触点印刷为微加工带来一系列的可能性。微触点印刷使之能形成仅由其成分的官能团加以区分的图形；这一能力使表面性质，如高精度的界面自由能的控制成为可能。在已有技术中，微触点印刷依赖于分子的自组装。利用自组装的单分子层，可生成(至少是部分地)接近于热动力学最小值和内在缺陷排除和自愈合的系统。以吸收材料或颗粒对表面污染进行最低限度的防护这种简单方法可使最终结构中的缺陷出人意料的降低。利用自组装单分子层的工艺可以在无防护的实验室大气中于大气压下进行。因此，利用自组装单分子层的微触点印刷适合用于不能照例使用惯常微加工设备、或其所使用的设备耗资巨大的实验室。图形化的自组装单分子层可设计成对于许多湿性化学腐蚀剂的保护层。
已有技术中，也有5到2000纳米厚的金膜通常被支撑在底层涂钛的Si/SiO2片或玻璃片上。钛起到金和支撑之间粘附促进剂的作用。但硅片是刚性，脆性，和不透光的。这些硅片还不适合于活版印刷，照相凹版印刷，胶版印刷，和网版印刷等大规模的，连续的印刷工艺(参见
印刷术基础，A.Glassman，Ed，(Tappi Press Atlanta，GA1981)；
不列颠大百科全书，vol.26，pp.76-92，110-111(Encyclopedia Brittanica，Inc.1991))。另外，硅必须在一个单独的步骤中用诸如Cr或Ti等粘结促进剂进行处理，否则Au将不能牢固粘结，无法形成一个稳定的和良好排序的单分子层。最后，硅对于可见光是不透明的，所以所得到的任何绕射图形一定是由反射光生成的，而不是透射光。
需要一种光学透明的，柔软基片上接触印刷图形化受体的方便，有效和简单的方法，该方法适合于连续加工，并且不使用自组装单分子层。这种方法和由该方法所形成的装置是简单的，且不受限于自组装单分子层的局限性而且便于制作。
本发明概述
本发明提供一种检测和定量分析存在于介质中的被分析物的低成本而又灵敏的装置和方法。该装置包括镀以金属膜，其上印制有被分析物-特性受体专门的预定图形。本发明不使用自组装单分子层，其更具普遍性的地方在于可以使用任何能够化学地偶合在所用表面上的受体。在接触到能够将光线散射到印制受体的塑料薄膜选定区域的目标被分析物时，通过被分析物的物理尺寸，折射指数和被分析物的确定的，精确地放置位置而产生透射光和/或反射光的衍射。在因被分析物过小或与周围介质相比不具备适合的折射率差使被分析物不能散射可见光的情况下，与被分析物偶合的聚合物小珠与受体的接触则为另一种产生光衍射的方法。可生成一个衍射图像，该图像可以很容易地用肉眼看到，或视需要可用一个传感设备看到。本发明为一种生物传感器，包括一个涂敷金属的聚合物薄膜，和印制在聚合物薄膜上的受体层，其中受体层上有可特定地粘合一种被分析物的受体材料。
本发明使用了图形化单分子层的接触印刷法，该单分子层利用微生物胶合剂衍生物。这种衍生物的一个实例为硫醇。所需要的胶合剂可以是硫羟化抗体或抗体片断，蛋白质，核酸，糖，碳水化合物，或任何其它能够粘合被分析物的功能性材料。衍生物吸附于金属表面，如镀以金属的聚合物薄膜。
图形化的单分子层可通过被分析物特异性受体图形在其上控制被分析物的放置。这样制作的本发明的生物传感装置使用时，首先将生物传感装置暴露于含有选定的被分析物的介质，随后，在一个适当的孕育期以后，由例如激光器或点光源发光穿过薄膜。如果介质中存在有被分析物并被粘合在图形化单分子层受体上，便生成可见光或近红外光图像的方式衍射光。换言之，上面粘合有被分析物的图形化单分子层能够产生光的衍射图形，根据单分子层上带有所研究的被分析物的受体的反应，该图形将有所不同。光线可能在可见光谱的范围内，并且不是由薄膜反射就是透射，而且被分析物可以是与所述单分子层反应的任何化合物或颗粒。光线可能是白光，或在优选可视范围内的单色电磁辐射。本发明还为黄金或其它适宜的金属与金属合金上的单分子层提供了柔性的支撑体。
本发明包括用于金或其它适合材料薄层的支撑体，这些材料在形成良好排序的单分子层或胶合物薄层时不需要粘合促进剂。本发明还为适合于连续印刷，而非分批制作的黄金或其它材料层提供了一种支撑体。另外，本发明提供了一种能够大批生产的低成本，易处理的生物传感器。本发明的生物传感器可以作为探测被分析物的单一试验装置进行生产，或设计成多种试验的装置。本发明的生物传感器的应用包括(但非局限于)探测衣物，如手巾中的化学或生物污染，通常用于探测预先包装的食物如果汁或其它饮料中被微生物污染的情况，以及本发明的生物传感器在健康诊断设备中的应用，如用于探测抗原，微生物，和血液成分的成套诊断组件。
在本发明的另一个实施例中，将特定微生物族的营养素加入受体的单分子层中。这样，浓度很低的微生物即可被探测到，即首先使本发明的生物传感器与加有的营养剂相接触，随后在适合于所粘合的微生物生长的条件下对生物传感器进行培育。微生物可以增长直到具有足够的微生物形成衍射图形。
本发明也可用于隐型眼镜，眼镜，窗户玻璃，药物玻璃瓶，溶剂容器，水瓶，邦迪等，探测其污染情况。
浏览了下述所公开的实施例的详细描述以后，将对本发明的这些和其它特性及优点看得更为清楚。
图1为带有营养剂敷层的镀以金属的MYLAR薄膜的示意说明。
图2为可以同时量测介质中几种不同被分析物的生物传感器。
图3为根据本发明的受体接触印制的示意图。
图4为以硫醇化抗体胶合物印制的表面上的酶联接免疫吸附剂测试(ELISA)。
图5为与印制的抗体接触后，涂有抗原的聚苯乙烯代用品颗粒的照片。
图6由图4所述样本所产生的衍射图形。
图7为连接于图形抗体受体的白色念珠菌的光学显微照片。
图8为白色念珠菌结合于图形受体上所产生的衍射图形。
发明详细介绍
本发明的特点在于改善生物传感装置，和使用这种生物传感装置的方法，用以探测和定量分析一种介质内所研究的被分析物是否存在和数量。可由本发明探测的被分析物包括(但非局限于)微生物，如细菌，酵母，真菌和病毒。与已有的装置不同，本发明的装置可以探测到介质中极少量的被分析物，仅需持续数分钟进行快速检定。另外，除光源以外，本发明的生物传感器不需要信号或相应的电子部件。
本发明包括将被分析物特异性受体微接触地印制在镀以金属的塑料薄膜上，它可用以开发基于光衍射以指示被分析物存在的一次性、易处理的生物传感器。在预定的被分析物与上面带有受体的塑料薄膜选定部位相接触时，通过被分析物的物理尺寸和被分析物确定的，精确的放置位置而产生透射光和/或反射光的衍射。例如酵母，真菌或细菌被放置在表面上有条理的图形中时，足以成为可见光的衍射元件。
除可产生简单的衍射图像以外，被分析物的图形还可用于开发全息传感图像和/或改变可视颜色。因此，一个全息图像的产生或已有全息图像颜色的改变会显示出阳性响应。由透射光衍射所生成的图形可以是任何形状，包括(但非限定于)根据粘合于受体材料的被分析物，将一个图形变换为另一个图形。在特殊优选的实施例中，被分析物与本发明的生物传感装置接触不足小时以后，衍射图形变得可以看清。
与被分析物相互作用产生光衍射的衍射光栅，必须有约1/2波长的最小周期性，并与周围介质之间具有实的或虚的折射率差。非常小的被分析物，诸如病毒或分子，可利用对该小分析物有特异性的较大颗粒间接探测到。在一个可探测到小型被分析物的实施例中，包括将颗粒，如乳胶小珠或聚苯乙烯小珠，用特异性粘附于所研究的被分析物的受体材料，如抗体来涂敷。在本发明中可以使用的颗粒包括(但非局限于)玻璃，纤维素，合成聚合物或塑料，乳胶，聚苯乙烯，聚碳酸酯，蛋白质，细菌或真菌细胞和类似物。颗粒需为球状，但颗粒的结构和空间的构形对于本发明不是很严格的。例如，颗粒可以是长条形，椭圆形，立方体，不规则形状等。合乎需要的颗粒尺寸的范围为直径约0.2μm到50μm，理想的是约0.4μm到1μm之间。颗粒的组成对于本发明不是严格的。
应明确最适宜的颗粒尺寸取决于颗粒的折射率和周围介质的折射率。为分析用于本发明透射图像中最适宜的颗粒尺寸的方法，使用下述方程：
topt＝λ/2(n2-n1)
其中
topt＝最佳颗粒高度
λ＝入射光波长
n2＝颗粒的折射率
n1＝周围介质的折射率
对于反射图像，颗粒的最佳高度为上述方程所得到的结果除以2。
镀有金属的薄膜上的单分子层含有一种特异性粘合于被分析物上抗原决定部位的受体材料或粘合剂，如抗体，该抗原决定部位与粘合颗粒所使用的抗原决定部位不同。因此，为探测带有如病毒颗粒等很小被分析物的介质时，首先将介质暴露于病毒颗粒可粘附其上的乳胶颗粒。随后，视需要清洗乳胶颗粒并暴露于带有含病毒特异性抗体的单分子层的镀有金属的薄膜。于是抗体与乳胶小珠上的病毒颗粒相粘结，从而将乳胶小珠以和单分子层一样的图形固定在薄膜上。由于被粘结的乳胶小珠将引起可见光的衍射，于是形成一个表明液体内有病毒颗粒存在的衍射图形。对于熟悉此项技术的人来讲利用颗粒的其它组合是众所周知的。
本发明的其它实施例中，受体，如抗体，被附着在这里所述的金属层上。随后将抗体暴露在含有粘结于受体的被分析物的环境中。在被分析物粘结在受体上之后，附加一个可识别金属结合的第二受体。在此第二受体上粘结酶或无机物，在添加一种或多种适当的试剂时，该酶或无机物可导致固体物质沉淀。例如，在存在有四甲基联苯胺的情况下，一种可使沉积形成的酶为过氧物酶(参见本文例3)。另一个实施例中，在有银的卤化物的情况下，使用胶体金。元素银将沉积在图形受体层上从而产生衍射图形。
可以利用本发明进行探测的被分析物包括(但非局限于)细菌；酵母；真菌；病毒；类风湿因子；抗体包括(但非局限于)IgG，IgM，IgA和IgE抗体；癌胚抗原；链球菌A族抗原；病毒抗原；与自免疫疾病有关的抗原，过敏源，肿瘤抗原；链球菌B族抗原，HIV I或HIVII抗原；或对于这些和其它病毒的宿主反应(抗体)；RSV特异性抗原，或对病毒的宿主反应(抗体)；抗原；酶；荷尔蒙；多糖；蛋白质；脂质；碳水化合物；药物或核酸；沙门氏菌类；念珠菌类，包括(但非局限于)白色念珠菌和念珠菌热带菌；脑膜炎奈瑟菌A，B，C，Y和W副135族，肺炎链球菌，大肠埃希杆菌，B型流感嗜血杆菌；由微生物衍生的抗原；半抗原；滥用药物；治疗药物；环境试剂；和肝炎特异性抗原。
本发明的另一实施例中，可以在单分子层中掺入特定族微生物的营养剂。这样，可以检测到很低浓度的微生物，即首先将本发明的生物传感器和掺入的营养剂相接触，随后在适当条件下对生物传感器进行培养，以使所粘附的微生物生长。在图1所示的一个实施例中，MYLAR薄膜15带有和MYLAR薄膜15背面相接触的营养剂敷层30。MYLAR薄膜15的相对面有位于其上的金属薄膜20。金属薄膜20优选为金。连接在金属薄膜20上的是对微生物具特异性的受体25。使用中，营养剂通过MYLAR薄膜慢慢地扩散。微生物接触到受体25时，所粘结的微生物吞食营养剂并滋长。微生物滋长后，将衍射其上的照射光形成衍射图形。因此，该实施例中，如果形成衍射图形，那就是由于所粘结的微生物生长了。当然，在某些情况下，微生物可能多得足以形成一个衍射图形，而不需要在图形单分子层上使用营养剂。
本发明的一部分是一种受体材料，该材料可以微印制在镀以金属的薄膜上并可特异性地粘结所研究的被分析物。因此，受体材料定义为一种特定的粘结配对中的一部分，配对包括(但非局限于)抗原/抗体，酶/底物，寡聚核苷酸/DNA，螯合物/金属，酶/抑制剂，细菌/受体，病毒/受体，荷尔蒙/受体，DNA/RNA，或RNA/RNA，寡核苷酸/RNA，这些类与任何其它类的粘合，以及这些类与无机类的相互作用。
粘附在附着层的受体材料的特点在于能够粘合所研究的一种或多种被分析物。可以用作受体材料的各种材料仅受限于选择性地与其从属配偶相结合的材料类型(对于任何被选择的样本而言)。属于受体材料总类别中的材料亚类包括毒素，抗体，抗体片断，抗原，荷尔蒙受体，寄生物，细胞，半抗原，代谢物，过敏源，核酸，核物质，自抗体，血蛋白，细胞屑，酶，组织蛋白，酶底物，辅酶，神经元传导体，病毒，病毒颗粒，微生物，蛋白质，多糖，螯合剂，药物，和任何其它特定粘结配对的成分。上面所列仅含有那些可以涂敷在附着层上以产生薄膜检定系统的许多不同材料中的某些材料。无论所选择的进行研究的被分析物是什么，受体材料应设计成能特异性和所研究的被分析物粘合的。
含有所研究的被分析物的基质可以是液体，固体，或气体，还可能包括体液如粘液，唾液，尿液，粪便物质，组织，骨髓，脑脊髓液，血清，血浆，全血，痰，缓冲液，提取液，精液，阴道分泌物，心包液，胃液，腹膜液，肋膜液。或其它冲洗液和类似物。所研究的被分析物可以是抗原，抗体，酶，DNA片断，完整的基因，RNA片断，小分子，金属，毒素，环境试剂，核酸，细胞质成分，长毛或鞭毛成分，蛋白质，多糖，药物，或任何其它如表A中所列出的材料。例如，可特异性粘结表面薄膜成分，蛋白质或脂质，多糖，核酸，或酶的细菌受体材料。特异性结合于细菌的被分析物可以是多糖，酶，核酸，薄膜元件，或对细菌作用作出反应由宿主所产生的抗体。被分析物的存在可能表明一种传染病(细菌的或病毒的)，癌症或其它代谢疾病或状态。被分析物的存在可能表示食物中毒或其它毒性的暴露。被分析物可能表示药物的滥用或可监视治疗药剂的水平。
可利用此项技术的一种最常遇到的检定调查为免疫试验。但一般考虑适合于核酸探测器，酶/底物，和其它配体/受体的试验模式。对于免疫试验，抗体可以起受体材料的作用，或可以是所研究的被分析物。受体材料，例如抗体或抗原，必须在试验装置的附着层上形成一个稳定，致密的反应层。如果抗原是被探测的而抗体为受体材料，抗体对所研究的抗原必须是特异性的；而抗体(受体材料)必须以足够的亲和力与抗原(被分析物)相粘结使抗原维持在试验表面上。在某些情况下，被分析物不是简单地粘结受体材料，但可使受体材料产生可探测的改善作用。这种相互作用可导致试验表面上物质增加或在试验表面上降低受体量。后者的一个例子如降解的酶或材料与一个特定的稳定底物的相互作用。在这一情况下，在与所研究的被分析物相互作用之前即可看到一个衍射图形，但如果有被分析物存在时衍射图形会消失。被分析物和受体材料产生粘结，杂化，或相互作用的具体机制对本发明不是重要的，但可能影响最后检查中使用的反应条件。
通常，受体材料为被动地以会产生衍射图形的一定图形粘结在附着层上。如果需要，由附着层引入试验表面游离官能团，可用于将受体材料共价附着于试验表面。如熟悉此项技术的人所周知的，受体材料的这种附着在化学上是可能的。
各种各样的工艺可用于将受体材料以一定的形式粘结在附着层上，在粘结所研究的被分析物时，当光线透过附着层时将形成一个衍射图形。试验表面可通过溶解作用将受体材料涂敷成离散的阵列或图形；通过喷镀、喷墨，或其它刻印方法；或由一种适当的溶剂系统进行旋涂。所选择的技术应使涂敷大量试验表面所需的受体材料数量最少，并能在使用过程中保持受体材料的稳定性/官能度。所使用的工艺必须以非常均匀和可再生的方式将受体材料涂布或粘附在附着层上。
受体层是由包含以下所选择的材料形成的，即抗原，抗体，寡核苷酸，螯合物，酶，细菌，细菌毛，细菌鞭毛物质，核酸，多糖，脂质，蛋白质，碳水化合物，金属，病毒，荷尔蒙和所说材料的受体。在优选实施例中，生物传感装置被制作和配置成可提供一个可用肉眼探测到的图形，该图形是所研究的被分析物夹在受体材料和从属粘结试剂之间时，对多色光传输所作出的响应。
存有被分析物的介质可能是固体，胶状，液体或气体。为探测体液中的被分析物，所述体液选自包括尿液，血清，血浆，脊髓液，痰，全血，唾液，尿路-生殖器官分泌物，粪便提取物，心包的，胃，腹膜，肋膜冲洗液，阴道分泌物，和喉咙擦抹物等，适宜的方法包括使用一种衍射仪以度量衍射图形的样式。可使用本发明的生物传感装置的最一般的气体为空气。
本发明的生物传感装置使用镀有金属的聚合物薄膜，最好是热塑聚合物薄膜上接触印制图形单分子层的方法，由此制成组合物，和使用这些组合物。图形单分子层使其上可控制地放置可能含有被分析物受体的液体。这里所使用的术语“其上的图形单分子层”意为镀有金属的聚合物薄膜上以任何图形出现的单分子层，包括固体图形。
当上面带有单分子层的薄膜暴露于可与单分子层起作用的一种被分析物时，薄膜将产生光学衍射图形，该图形根据单分子层与所研究的被分析物的作用而有所不同。液体可是高表面张力的流体，如水。光线可在可视光谱范围内，并且可以是由薄膜反射的，或是穿过薄膜透射的，被分析物可以是任何与单分子层起作用的化合物。
在一个优选实施例中，该方法包括将底物与可能包含被分析物的试验样本相接触，接触是在底物可能改变单分子层的折射率的条件下进行的。当光线透过带有单分子层的镀有金属的热塑聚合物时，形成可视图形，并可将光线导向表面进行观看，或透过底物直接观看。
在一个实施例中，本发明采用标尺的形式，其中微接触印制的镀有金属的薄膜连接在该标尺的端部。使用时将标尺浸入液体中，认为该液体有被分析物存在，使其保持数分钟。随后将标尺移开，然后或是光线投射透过镀有金属的薄膜，或是以薄膜后面的光线观察该薄膜。如果看到一个图形，则认为液体中有被分析物存在。
本发明的另一个实施例中，在同一个支撑体上构造多个被分析物试验。如图2所示，配置带有几个微接触印制的镀有金属的薄膜70，75，80和85的长条状物50，每个薄膜有一个其上印制的单分子层图形60。每个微接触印制的镀有金属的薄膜70，75，80，和85具有不同的受体材料，这些材料因被分析物的不同而不同。可以看出，可设计成带有各种微接触印制的镀有金属的薄膜的阵列，从而使本发明生物传感器装置的使用者在一种介质中利用一个单独的试验探测多种被分析物的存在。
本发明的又一个实施例中，生物传感器可以附着在一个背后粘的棍上，随后将其放置在一个坚硬的表面或容器壁上。生物传感器可以放置在容器的内表面上，如食物的包装或玻璃瓶内表面。随后可对生物传感器进行观察，以确定是否有微生物，污染。
在本发明的一个实施例中，受体层具有如下的一般式：
X-R-Y
X是与金属或金属氧化物反应的活性基。例如，X可以是不对称或对称的二硫化物(-R’SSR，-RSSR)，硫化物(-R’SR，-RSR)，二硒化物(-R’Se，-SeR)，硒化物(-R’SeR，-RSeR)，硫醇(-SH)，腈(-CN)，异腈，硝基(-NO2)，硒醇(-SeH)，三价磷化合物，异硫氰酸盐，黄原酸盐，硫代碳酸盐，磷化氢，硫代酸或二硫代酸，羧酸，羟基酸，和异羟肟酸。
R为连接基，它可以视需要被杂原子隔断，并优选为非支链的以便优化密集充填。该连接基有助于防止空间位阻和/或增强Y的活性。
Y为赋予受体层官能度的分子。Y可以是任何可以优选地粘结所研究的被分析物的分子。Y可以是毒素，抗体，抗体碎片抗原，荷尔蒙受体，寄生物，细胞，半抗原，代谢物，过敏源，核酸，核物质，自抗体，血蛋白，细胞碎屑，酶，组织蛋白，酶底物，辅酶，神经元递质，病毒，病毒颗粒，微生物，蛋白质，多糖，螯合物，药物，和任何其它特定的粘结配对的成分。
一种理想的与可能的粘合剂，如抗体或抗体碎片起作用，以提供官能度X的试剂包括(但非局限于)磺基-LCSPDP(Pierce chemical Co.Rockford，IL)，它具有如下的分子式：
磺基-LC-SPDP对于硫氢基和氨基起作用，因而理想地适合于和蛋白质反应，如抗体或其它蛋白受体，蛋白多糖，脂肪蛋白，糖蛋白质，或氨基糖包括(但非局限于)葡萄糖胺或半乳糖胺。
在一个典型的试验方法中，如图3所示，一种用光刻法制作的靠膜被放置在玻璃或塑料的佩特里培养皿中，比例为10∶1(w∶w或v∶v)的SYLGARD硅酮高弹体184和SYLGARD硅酮高弹体184固化剂(Dow Corning Corporation)混合液倾注其上。该高弹体可在室温下搁置约30分钟，并减压排气，随后在60℃温度下固化4到16小时，并从靠膜轻轻剥离出。
高弹体印模的“涂墨”是将高弹体印模模具浸泡在浓度约为0.1mG/mL到约0.5mG/mL的受体“墨水”中约10秒到10分钟，接着在氮气中干燥印模。可以在周围环境的条件下或暴露于氮气流中一直干燥到印模表面上用肉眼看不到液体(通常约60秒)为止。涂墨以后，将印模施加(通常用手)镀有金属的表面。以非常轻的手部压力使印模和表面之间完全接触。印模置于该表面最好约10秒到约200秒。印模置于表面上的实际时间将随所使用的墨水而不同。随后由表面上轻轻取下印模。优选实施例在受体印制之后将随着一个钝化步骤以覆盖不包含粘结受体的所有的金属表面。钝化有助于非特异性被分析物的粘结。
印模的高弹体的特性对方法的成功是重要的。聚二甲基硅氧烷(PDMS)固化时具有充分的弹性，甚至在表面带有明显的凸纹的情况下，也使印模和表面有良好的贴合接触；这种接触对于有效地接触传递受体“墨水”到金膜来讲是重要的。PDMS的弹性在印模由靠膜移走时也是重要的：如果印模(和靠膜一样)是刚性的，固化后如果不破坏两个基体中的一个是很难将印模和靠膜分开的。PDMS也要有足够的刚性，甚至在尺寸为亚微米时，也可保持其形状。能成功地生成线条宽度小到200nm的图形。PDMS的表面有较低的界面自由能(y＝22.1dynes/cm)，同时印模不会牢固地粘结在镀有金属的薄膜上。印模的耐久性在于一个印模可以在数月期间使用100次其效能也不会明显降低。PDMS的弹性在涂墨过程中能使印模吸附烷烃硫醇墨水而不明显溶胀也起着重要作用。可以在印刷滚筒上制作印模以便能进行连续的印制操作。
随后将对本发明的方法和构成作更为详细的说明。这里所引用的所有出版物都将其全部引入作为参考。
所有其上能够涂敷金属垫层的热塑性薄膜都适用于本发明。它们包括(但非局限于)聚合物，如：聚对苯二甲酸乙二醇酯(MYLAR)，丙烯腈-丁二烯-苯乙烯，丙烯腈-丙烯酸甲酯共聚物，赛璐玢，纤维素聚合物，如乙基纤维素，乙酸纤维素，乙酸丁酸纤维素、丙酸纤维素，三乙酸纤维素，聚乙烯、聚乙烯-乙酸乙烯酯共聚物，离子交联聚合物(乙烯聚合物)聚乙烯-尼龙共聚物，聚丙烯，甲基戊烯聚合物，聚氟乙烯，和芳香聚砜。优选塑料薄膜有大于80％的光学透明度。其它适合的热塑性塑料和供应商可由参考著作，如现代塑料制品百科全书(McGraw-Hill Publishing Co.，New York 1923-1996)中找到。
本发明的一个实施例中，上面带有金属涂层的热塑性薄膜具有约5％和95％的光学透明度。用于本发明热塑性薄膜最理想的光学透明度在约20％和80％之间。本发明的一个理想的实施例中，热塑性薄膜具有至少约80％的光学透明度，而金属涂层的厚度应使光学透明度保持在约20％以上，从而可由反射或透射光产生衍射图形。这相当于金属涂层厚度约为20nm。但本发明的其它实施例中，金的厚度可以在约1nm和1000nm之间。
覆盖在薄膜上的优选金属为金。但银，铝，铬，铜，铁，锆，白金和镍，以及这些金属的氧化物都可以使用。铬的氧化物可用以制作镀金属层。
原则上，任何带有适当尺寸波纹的表面可用作靠膜。微接触印制工艺开始时用适合铸造高弹体印模的凸纹结构。该“靠膜”模板可以用光刻法制作，或用其它工艺，如商用的衍射光栅。在一个实施例中，印模由聚二甲基硅氧烷橡胶制作。
在一个实施例中，本发明的特点在于一种光学试验装置，该装置具有一个构形和安排成能同时对表面上所研究的一种被分析物的许多样本进行试验的光学活性受体表面，和一个自动的液体操作装置(例如，一个吸管装置)，该装置设计安排成能够将样本和试剂溶液配送到表面上。
本发明具有广泛的用途，并可用于各种特异性粘合配对试验方法。例如，本发明的装置可用于探测抗原或抗体的免疫试验方法。装置适合于用在直接，间接，或竞争探测模式中，用以确定酶的活性，和探测微小的有机分子(例如，滥用药物，治疗药物，环境试剂)，以及核酸的探测。
印模可以在空气中使用，或在液体，如水中使用、以防止烷烃硫醇的过分扩散。对于大规模或连续的印制过程，最理想的是在空气中印制，因为对这些工艺来讲希望较短的接触时间。
本发明的一个实施例中，图形是在镀有金属的热塑聚合物上与受体层一起形成的。本发明的其它实施例中，图形的凸纹和受体层一起形成。在印模压制工序之后，塑料上镀有金属的区域可视需要进行钝化，例如，用一种甲基封端的单分子层如十六基硫醇进行。
本发明进一步由下述的实施例进行说明，但并不以任何形式构成对本发明范围的限制。相反，可以清楚地看出，在阅读了这里的说明以后，熟悉此项技术的人，将会在不脱离本发明精神的情况下，根据本发明方法得出各种实施例，改进，及其等价物。
实施例1
大肠埃希杆菌0157：H7(Kirkegaard & Perry Labs)抗体衍生物的实例如下：在1mG的抗体中加入450μL磷酸盐缓冲盐水(PBS)和50μL的10mM磺基-LC-SPDP(Pierce Catalog#21650)水溶液。室温下于60分后，将溶液在D-SaltTM聚丙烯酰胺脱盐柱(Pierce，Rockford，IL)中脱盐。如果随后将进行二硫化物的还原将使用一种pH为4.5的乙酸盐缓冲剂，如果抗体衍生物作为二硫化物保留，将使用pH为7.5的PBS缓冲剂。自柱中收集500μL的馏分，利用一种CoomassiePlus Protein Assay对含有抗体衍生物的该含馏分进行测定。
实施例2
将由实施例1所得的硫羟化抗体，是二硫化物或是硫醇，接触印刷在金涂敷的MYLAR上。将高弹体印模浸入浓度为0.5mG/mL的硫羟化抗体中10分钟，随后在氮气下使印模进行干燥，并与金涂敷的MYLAR薄膜接触10-120秒。
实施例3
在该实施例中，示出一种光线聚集图形。实施例2中所述的印制以后无图形区域将与另一种硫醇，如十六烷硫醇起作用。聚集图形被保留，表明硫羟化抗体被化学吸附并未被置换。在印刷区域，印刷表面的酶联免疫吸附剂试验(ELISA)为阳性的，证实了图形中活性抗体的存在(图4)。该ELISA试验使用了一种与实施例1中所使用的大肠埃希杆菌特异性抗体结合的过氧化物酶。沉积在图形抗体夹层上的N-四甲联苯胺生成衍射图形。被抗原改性的聚苯乙烯代用品颗粒表面也对受体层产生图形化吸收。N-四甲联苯胺沉积物生成的衍射图形示于图6。
实施例4
聚苯乙烯代用品颗粒是用惯常的技术由大肠埃希杆菌0157：H7抗原(Kirkegarrd & Perry Labs，Cat#50-95-90)的乙基二甲基氨基二碳化二亚胺(EDAC-Sigma Chemical Company，St.Louis，MO)与碳化二亚胺偶合于一微米的聚苯乙烯乳胶球上形成的。2wt％的二亚胺溶液与羧化物改性的PS乳胶(Bangs：1010颗粒/mL)起作用4小时，随后将这些活性颗粒放置在400uG/mL的抗原溶液中。该代用品稀释到108颗粒/mL，被暴露于含有图形大肠埃希杆菌0157：H7抗体的传感器60分钟，该抗体是如实施例2所描述进行生产的。在用磷酸盐缓冲剂清洗之后，将样本干燥，进行照相(图5)证明产生如实施例3所述的衍射图形。
实施例5
已经明确地确立关于自组装单分子层(SAM)存在的准则为对化学刻蚀剂抗性的增加，而烷烃硫醇自组装单分子层为金提供了对氰化物的抗蚀刻性。实施氰化物蚀刻以测定硫羟化蛋白质或本发明的寡核苷酸粘合剂在金上是否形成保护的SAM。金涂敷的聚合物薄膜(35nM黄金厚度)被暴露于白色念珠菌(0.5mG/mL)的硫羟化抗体，硫羟化蛋白G(0.5mG/mL)，硫羟化寡核苷酸(10μM)，或是白色念珠菌非衍生的抗体(仅为物理吸附；0.5mG/mL)的水溶液中；一种周知的可在金上形成SAM的十六烷硫醇(HDT；5.7mM)乙醇溶液被用来作为阳性对照。在暴露于含有粘合剂的硫醇中16小时以后，带涂层的金样本被移出，用溶剂(水或乙醇)彻底清洗，并在氮气流下干燥。
用粘合剂涂敷的样本被浸入含有氢氧化钾(0.5M)的氰化钾水溶液(100mM)中，同时以空气(氧气)鼓泡进入溶液。在蚀刻11分钟后，将样本移出，用水漂洗，并用肉眼评估留下的金量。表1汇总了观察的结果。HDT样本是仅有的能使大多数黄金留在其表面上的样本。硫羟化抗体具有很少量的金(≈5％覆盖率)，而其它样本在蚀刻以后没有留下黄金。这表明和HDT不同，使用硫羟化粘合剂制备光学衍射生物传感器不会形成防护的SAM。
表1-氰化物蚀刻试验总结
| 样本 | 蚀刻后的观测值 |
| 十六烷硫醇(HDT) | 70-80％ |
| 硫羟化抗体 | ～5％(随机斑点) |
| 抗体(物理吸附在表面上) | 无金存留 |
| 硫羟化蛋白质G | 无金存留 |
| 硫羟化寡核苷酸 | 无金存留 |
实施例6
带有图形化白色念珠菌抗体的样本以如下方法制备：将金/聚酯(10nM金厚度)浸入5mG/mL的β酪蛋白(Sigma catalog#C6905)的磷酸盐-缓冲盐水溶液中10分钟。样本用蒸馏水彻底漂洗，在强氮气流下干燥。利用带有10微米直径圆形x，y阵列的聚二甲基硅氧烷印模进行接触印刷。通过将印模浸入0.5mG/mL抗体衍生物的水溶液中将印模涂敷白色念珠菌硫羟化抗体(初始的多细胞系抗体为FitzgeraldIndustries International，Inc.，Concord，MA所生产的Catalog#20-CR04)。10分钟后，取出印模并利用强氮气流进行彻底干燥。完成了在酪蛋白处理样本上的接触印刷，其暴露的时间为1秒到2分钟较为适宜。两分钟是优选的接触时间。印制以后，样本再次用蒸馏水漂洗并进行干燥。
通过在带状成人前臂皮肤上接种浓度为每毫升106酵母细胞，并将传感器放置在含酵母的带上，而将传感器样本暴露于试管携带的病菌白色念珠菌细胞。酵母细胞传递到传感器仅需数秒钟的接触(图7)即可完成。酵母细胞图形化地粘结到传感器上由显微镜分析所认定，用激光器照射时得出一个衍射图形(图8)。
曾经接种过试管携带的病原菌白色念珠菌细胞的其它表面为琼脂板和HUGGIESBaby Wipe。这些表面暴露于抗体为基底的传感器也会得到细胞的图形化附着和产生衍射图形。
熟悉此项技术的人现在可以看到，对于所述的实施例在不脱离本发明的精神的情况下可作出对这里所公开的本发明的某些修改。在以上就优选实施例对本发明进行描述的同时，本发明自然适合于作大量的重新安排，修改，和改良，所有这些安排，修改，和改良都在所附权利要求的范围之内。
Claims (63)
1.一种生物传感器，包括：
用金属涂敷的聚合物薄膜；和
直接印制在聚合物薄膜上的图形受体层，其中受体层上具有可特异性粘合一种被分析物的受体材料；
其中，受体层所印制的图形，应在生物传感器粘结被分析物时，使该生物传感器能将透射或反射光衍射形成肉眼可见的衍射图形。
2.根据权利要求1所说的生物传感器，其特征在于衍射图形形成全息图。
3.根据权利要求1所说的生物传感器，其特征在于金属为金，银，铬，镍，铂，铝，铁，铜，三氧化二铬或锆。
4.根据权利要求3所说的生物传感器，其特征在于金属为金。
5.根据权利要求3所说的生物传感器，其特征在于金属涂层的厚度在约1纳米至1000纳米之间。
6.根据权利要求1所说的生物传感器，其特征在于聚合物薄膜为聚对苯二酸乙二醇酯，丙烯腈-丁二烯-苯乙烯，丙烯腈-丙烯酸甲酯共聚物，赛璐玢，纤维素聚合物，如乙基纤维素，乙酸纤维素，乙酸丁酸纤维素，丙酸纤维素，三乙酸纤维素，聚乙烯，聚乙烯-乙酸乙烯酯共聚物，离子交联聚合物(乙烯聚合物)聚乙烯-尼龙共聚物，聚丙烯，甲基戊烯聚合物，聚氟乙烯，和芳香聚砜。
7.根据权利要求6所说的生物传感器，其特征在于聚合物薄膜为聚对苯二酸乙二醇酯。
8.根据权利要求1中所说的生物传感器，其特征在于聚合物薄膜为光学透明的。
9.根据权利要求1所说的生物传感器，其特征在于聚合物薄膜的光学透明度在约5％至95％之间。
10.根据权利要求1所说的生物传感器，其特征在于聚合物薄膜的光学透明度在约20％至80％之间。
11.根据权利要求1所说的生物传感器，其特征在于图形受体层是由下式的化合物形成的：
X-R-Y
其中：
X是与聚合物薄膜上的金属或金属氧化物起反应的活性基；
R为视需要存在的连接基；和
Y为具有所研究的任何特性的化合物。
12.根据权利要求11所说的生物传感器，其特征在于R为0至12个碳原子长度。
13.根据权利要求11所说的生物传感器，其特征在于X为由包括下式的化合物所生成的：
14.根据权利要求1中所说的生物传感器，其特征在于被分析物为细菌，酵母，真菌，病毒，类风湿因子，IgG，IgM，IgA和IgE抗体，癌胚抗原，链球菌A族抗原，病毒抗原，与自免疫疾病有关的抗原，过敏源，肿瘤抗原，链球菌B族抗原，HIV I或HIV II抗原，抗体病毒，RSV特异性抗原，抗体，抗原，酶，荷尔蒙，多糖，蛋白质，脂质，碳水化合物，药物或核酸，脑膜炎奈瑟菌A，B，C，Y和W副135族，肺炎链球菌，大肠埃希杆菌K1，B型流感嗜血杆菌，由微生物衍生的抗原，半抗原，滥用药物，治疗药物，环境试剂，和肝炎特异性抗原。
15.根据权利要求14所说的生物传感器，其特征在于被分析物为细菌，酵母，真菌或病毒。
16.根据权利要求1所说的生物传感器，其特征在于受体材料为抗原，抗体，核苷酸，螯合剂，酶，细菌，酵母，真菌，病毒，细菌纤毛，细菌鞭毛物质，核酸，多糖，酯质，蛋白质，碳水化合物，金属，荷尔蒙和所说的物质的受体。
17.根据权利要求16所说的生物传感器，其特征在于真菌为念珠菌类。
18.根据权利要求16所说的生物传感器，其特征在于细菌为沙门氏菌类。
19.根据权利要求1所说的生物传感器，其特征在于该生物传感器附着于容器的内壁上。
20.根据权利要求19所说的生物传感器，其特征在于容器为小瓶。
21.根据权利要求18所说的生物传感器，其特征在于容器为食品容器。
22.根据权利要求1所说的生物传感器，其特征在于生物传感器附着于衣物的内侧。
23.根据权利要求21所说的生物传感器，其特征在于衣物为尿布。
24.根据权利要求1所说的生物传感器，其特征在于被分析物附着在颗粒上。
25.根据权利要求24所说的生物传感器，其特征在于颗粒由玻璃，纤维素，乳胶，聚苯乙烯，聚碳酸酯，蛋白质，或微生物细胞组成。
26.根据权利要求24所说的生物传感器，其特征在于颗粒为约0.2nm至50nm。
27.根据权利要求26所说的生物传感器，其特征在于颗粒为约0.4μm至1μm。
28.根据权利要求26所说的生物传感器，其特征在于颗粒的粒度是由以下公式确定的：
topt＝λ/2(n2-n1)
其中
topt＝最佳颗粒高度
λ＝入射光波长
n2＝颗粒的折射率
n1＝周围介质的折射率。
29.探测被分析物的方法，包括：
将该被分析物与生物传感器相接触，该生物传感器的基本组成为：
涂有金属的聚合物薄膜，和
直接印制在聚合物薄膜上的图形受体层，其中受体层上具有能特异性与被分析物粘合的受体材料；
使光线穿过生物传感器或由生物传感器反射；
其中，受体层所印制的图形，应在生物传感器粘结被分析物时，使该生物传感器能将透射或反射光衍射形成肉眼可见的衍射图形。
30.根据权利要求29所说的方法，其特征在于衍射图形形成全息图。
31.根据权利要求29所说的方法，其特征在于金属选自金，银，铬，镍，铂，铝，铁，铜，三氧化二铬或锆。
32。根据权利要求31所说的方法，其特征在于金属为金。
33.根据权利要求31所说的方法，其特征在于金属涂层厚度为约1纳米至1000纳米之间。
34.根据权利要求29所说的方法，其特征在于聚合物薄膜为聚对苯二酸乙二醇酯，丙烯腈-丁二烯-苯乙烯，丙烯腈-丙烯酸甲酯共聚物，赛璐玢，纤维素聚合物，如乙基纤维素，乙酸纤维素，乙酸丁酸纤维素，丙酸纤维素，三乙酸纤维素，聚乙烯，聚乙烯-乙酸乙烯酯共聚物，离子交联聚合物(乙烯聚合物)聚乙烯-尼龙共聚物，聚丙烯，甲基戊烯聚合物，聚氟乙烯，和芳香聚砜。
35.根据权利要求34所说的方法，其特征在于聚合物薄膜为聚对苯二酸乙二醇酯。
36.根据权利要求29所说的方法，其特征在于聚合物薄膜为光学透明的。
37.根据权利要求29所说的方法，其特征在于聚合物薄膜的光学透明度在5％和95％之间。
38.根据权利要求29所说的方法，其特征在于聚合物薄膜的光学透明度在约20％和80％之间。
39.根据权利要求29所说的方法，其特征在于图形受体层是由下式的化合物所形成的：
X-R-Y
其中：
X是与聚合物薄膜上的金属或金属氧化物起反应的活性基；
R为视需要存在的连接基；和
Y为具有所研究的任何特性的化合物。
40.根据权利要求39所说的方法，其特征在于R为0至12个碳原子长度。
41.根据权利要求39所说的方法，其特征在于X为由包括下式的化合物生成的：
42.根据权利要求29所说的方法，其特征在于被分析物为细菌，酵母，真菌，病毒，类风湿因子，IgG，IgM，IgA和IgE抗体，癌胚抗原，链球菌A族抗原，病毒抗原，与自免疫疾病有关的抗原，过敏源，肿瘤抗原，链球菌B族抗原，HIV I或HIV II抗原，抗体病毒，RSV特异性抗原，抗体，抗原，酶，荷尔蒙，多糖，蛋白质，脂质，碳水化合物，药物或核酸，脑膜炎奈瑟菌A，B，C，Y和W副135族，肺炎链球菌，大肠埃希杆菌K1，B型流感嗜血杆菌，由微生物衍生的抗原，半抗原，滥用药物，治疗药物，环境试剂，和肝炎特异性抗原。
43.根据权利要求42所说的方法，其特征在于被分析物为细菌，酵母，真菌或病毒。
44.根据权利要求43所说的方法，其特征在于真菌为念珠菌类。
45.根据权利要求43所说的方法，其特征在于细菌为沙门氏菌类。
46.根据权利要求29所说的方法，其特征在于受体物质为抗原，抗体，核苷酸，螯合剂，酶，细菌，酵母，真菌，病毒，细菌纤毛，细菌鞭毛物质，核酸，多糖，脂质，蛋白质，碳水化合物，金属，荷尔蒙和所说物质的受体。
47.根据权利要求29所说的方法，其特征在于生物传感器附着于容器的内壁。
48.根据权利要求47所说的方法，其特征在于容器为小瓶。
49.根据权利要求48所说的方法，其特征在于容器为食物容器。
50.根据权利要求29所说的方法，其特征在于生物传感器附着于衣物的内侧。
51.根据权利要求50所说的方法，其特征在于衣物为尿布。
52.根据权利要求29所说的方法，其特征在于被分析物附着在颗粒上。
53.根据权利要求52所说的方法，其特征在于颗粒由玻璃，纤维素，乳胶，聚苯乙烯，聚碳酸酯，蛋白质，或微生物细胞组成。
54.根据权利要求52所说的方法，其特征在于颗粒为约0.2nm至50nm之间。
55.根据权利要求54所说的方法，其特征在于颗粒为约0.4μm至1μm之间。
56.根据权利要求52所说的方法，其特征在于颗粒的粒度由以下公式确定：
topt＝λ/2(n2-n1)其中
topt＝最佳颗粒高度
λ＝入射光波长
n2＝颗粒的折射率
n1＝周围介质的折射率。
57.制作生物传感器的方法，包括以图形形式在涂有金属的聚合物薄膜上涂布受体层，以便被分析物粘结在图形受体层时，使图形受体层形成衍射图像。
58.探测被分析物的方法，包括
a.使被分析物与生物传感器相接触，所述生物传感器的基本组成为：
涂敷有金属的聚合物薄膜；和
直接印制在聚合物薄膜上的图形受体层，其中受体层上具有第一受体物质，该物质能特异性粘结该被分析物，形成被分析物/第一受体物质共轭物；
b.将带有被分析物/第一受体物质共轭物的生物传感器与第二受体物质相接触，该物质能特异性地与被分析物/第一受体物质共轭物相粘结，其中第二受体物质与形成沉淀的材料共轭；
c.将步骤b的生物传感器与可产生沉淀的试剂相接触；
d.使光线穿过生物传感器或由生物传感器反射；其中，受体层所印制的图形，应在生物传感器粘结被分析物时，使该生物传感器能将透射光或反射光衍射形成肉眼可见的衍射图形。
59.根据权利要求58所说的方法，其特征在于形成沉淀的材料为过氧化物酶或胶体金。
60.根据权利要求58所说的方法，其特征在于试剂为N-四甲联苯胺或卤化银。
61.根据权利要求58所说的方法，其特征在于第二受体材料对第一受体材料是特异性的。
62.根据权利要求58所说的方法，其特征在于第一受体材料为与酶共轭的抗体。
63.根据权利要求58所说的方法，其特征在于第二受体材料为抗体。
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| US08/991,644 US6060256A (en) | 1997-12-16 | 1997-12-16 | Optical diffraction biosensor |
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| FR2730810B1 (fr) * | 1995-02-21 | 1997-03-14 | Thomson Csf | Capteur chimique hautement selectif |
| EP0812434B1 (en) * | 1995-03-01 | 2013-09-18 | President and Fellows of Harvard College | Microcontact printing on surfaces and derivative articles |
| US5736257A (en) * | 1995-04-25 | 1998-04-07 | Us Navy | Photoactivatable polymers for producing patterned biomolecular assemblies |
| US5830539A (en) * | 1995-11-17 | 1998-11-03 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon | Methods for functionalizing and coating substrates and devices made according to the methods |
| US6020047A (en) * | 1996-09-04 | 2000-02-01 | Kimberly-Clark Worldwide, Inc. | Polymer films having a printed self-assembling monolayer |
| US5922550A (en) * | 1996-12-18 | 1999-07-13 | Kimberly-Clark Worldwide, Inc. | Biosensing devices which produce diffraction images |
-
1997
- 1997-12-16 US US08/991,644 patent/US6060256A/en not_active Expired - Lifetime
-
1998
- 1998-12-16 CN CNB988122553A patent/CN1171083C/zh not_active Expired - Fee Related
- 1998-12-16 KR KR1020007005534A patent/KR100568635B1/ko not_active IP Right Cessation
- 1998-12-16 WO PCT/US1998/026759 patent/WO1999031486A1/en active IP Right Grant
- 1998-12-16 AU AU19205/99A patent/AU760500B2/en not_active Ceased
- 1998-12-16 EP EP98963991A patent/EP1040338B1/en not_active Expired - Lifetime
- 1998-12-16 CA CA2309595A patent/CA2309595C/en not_active Expired - Lifetime
- 1998-12-16 DE DE69838815T patent/DE69838815T2/de not_active Expired - Lifetime
- 1998-12-16 ES ES98963991T patent/ES2294826T3/es not_active Expired - Lifetime
-
2000
- 2000-02-11 US US09/503,554 patent/US6436651B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US6060256A (en) | 2000-05-09 |
| ES2294826T3 (es) | 2008-04-01 |
| DE69838815T2 (de) | 2008-04-03 |
| CA2309595C (en) | 2010-03-30 |
| AU760500B2 (en) | 2003-05-15 |
| AU1920599A (en) | 1999-07-05 |
| EP1040338A1 (en) | 2000-10-04 |
| DE69838815D1 (de) | 2008-01-17 |
| KR20010032322A (ko) | 2001-04-16 |
| WO1999031486A1 (en) | 1999-06-24 |
| CA2309595A1 (en) | 1999-06-24 |
| US6436651B1 (en) | 2002-08-20 |
| EP1040338B1 (en) | 2007-12-05 |
| KR100568635B1 (ko) | 2006-04-07 |
| CN1286753A (zh) | 2001-03-07 |
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